CN108203439A - Stibazole compounds, preparation method and use - Google Patents
Stibazole compounds, preparation method and use Download PDFInfo
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- CN108203439A CN108203439A CN201611181281.0A CN201611181281A CN108203439A CN 108203439 A CN108203439 A CN 108203439A CN 201611181281 A CN201611181281 A CN 201611181281A CN 108203439 A CN108203439 A CN 108203439A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Abstract
The invention discloses a kind of novel Stibazole compounds（I）And its pharmaceutically acceptable salt, preparation method, pharmaceutical composition and the purposes in treatment and/or prevention nervus retrogression relevant disease drug is prepared, including but not limited to neurodegenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma；
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of novel Stibazole compounds（I）And its pharmaceutically may be used
The salt of receiving, preparation method, pharmaceutical composition and in treatment and/or prevention nervus retrogression relevant disease drug is prepared
It is purposes, including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, more
The neurodegenerative diseases such as hair property sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Background technology
Alzheimer's disease（Alzheimer ' s disease, AD, senile dementia）Be one kind with progressive cognitive disorder
With the central nervous system degenerative disease based on memory damage, incidence becomes in ascendant trend year by year and is only second to the heart
The frequently-occurring disease of angiosis and cancer has gone up the 4th for the cause of death in developed countries such as America and Europes.According to world health
Organisation Report, global over-65s old man have 10% dysnoesia, and wherein half occurs dull-witted, falls ill within 85 years old or more
Rate nearly 50%.The AD patient numbers about 600-700 ten thousand in China, incidence are more than 5%.With adding for population in the world aging process
Soon, incidence is in apparent ascendant trend, is announced according to Alzheimer's Disease International in December, 2013
's《The global implication of Alzheimer's disease：2013-2050》It is pointed out in report, AD will face most as the coming few decades whole world
Big Health challenges, to the year two thousand thirty, patient numbers will rise to 76,000,000 by 44,000,000 in 2013, to the year two thousand fifty, this numerical value
It is up to surprising 1.35 hundred million.Due to AD clinical manifestations for memory capability, capacity of orientation, thinking and judgement decline and
Activity of daily living reduces or even occurs abnormal Behavioral and psychological symptom etc., makes patient care difficulty larger, to society and family's band
Carry out heavy burden.The drug that approved is used to treat light/moderate AD at present has acetylcholinesterase（AChE）Inhibitor, Yi Jiyong
In severe AD treatmentsNMethyl-DAspartic acid（NMDA）Receptor antagonist, but Clinical practice shows that these drugs can pass through
It improves patient's body levels of acetylcholine or the exitotoxicity of excitatory amino acid is inhibited to alleviate AD symptoms, but cannot be effective
Prevent or reverse the course of disease, but also can cause hallucinations, misunderstanding, dizziness, headache, nausea, hepatotoxicity, loss of appetite and
The serious toxic side effect such as stool frequency, thus long-term efficacy is not satisfactory.Therefore, clinically there is an urgent need to research and develop with novel work
With the AD medicines of mechanism.
AD belongs to disease caused by many factors, and pathogenesis is complicated, does not illustrate its pathogenesis completely also so far, but study
Show patient's intracerebral levels of acetylcholine decline,βThe excessive generation and deposition, metal ion metabolism of amyloid protein are disorderly
Disorderly, Ca2+Dysequilibrium,tauNeurofibrillary tangles caused by protein hyperphosphorylation, monoamine oxidase B（MAO-B）Activity increases
By force, glutamate receptor activity is excessively high, oxidative stress generates a large amount of active oxygens（ROS）It is more with free radical and Neuroinflammation etc.
Kind factor is played an important role in the pathogenic process of AD.For above-mentioned pathogenic factors, researcher is using a traditional " medicine one
Target " drug design strategies, it was found that largely there is high activity and highly selective drug to a certain target spot, such as：Cholinesterase presses down
Preparation andNMethyl-DAspartate receptor agonist etc., but these drugs secondary are made there are action target spot is single, Clinical practice is malicious
With it is more, not good enough to the long-term efficacy of AD patient the problems such as.
In recent years, with constantly illustrating to AD pathogenesis, finding the occurrence and development of AD has multimachine system, multifactor
It is the characteristics of effect, again interrelated between different mechanisms to influence each other, constitute complicated network during AD occurrence and development
Regulator control system.Based on the above results, researcher proposes " multiple target point targeted drug "（Multitarget-directed
Ligands, MTDLs）Strategy researches and develops anti-neurodegenerative disease drug.So-called " multiple target point drug " refers to that single chemistry is real
Body acts on multiple target spots in disease network simultaneously, and synergistic effect can be generated to the effect of each target spot, is more than gross effect each
Single-action the sum of is answered, and such medicine is also referred to as " Multifunctional " or " Multipotential " drug.Multiple target point drug with it is more
Medicine use in conjunction and the main distinction of compound medicine are：Dosage can be reduced, therapeutic effect is improved, avoids between drug
Interaction and the toxic side effect thus brought, uniform pharmacokinetic properties, be easy to use etc..It designs and finds have simultaneously
Have and inhibit monoamine oxidase B, anti-oxidation stress, and the more balanced multiple target point AD medicines of multiple biological activities are current grind
Study carefully hot spot.Therefore, research and development are with novel chemical structure, novel mechanism of action, and have multiple target point（It is or multi-functional）Effect,
The anti-neurodegenerative disease therapeutic agent of less toxic side effect not only conforms with the active demand of social senilization's process, and has
Good market prospects.
Invention content
Present invention aims at open a kind of novel Stibazole compounds（I）It is and its pharmaceutically acceptable
Salt；
Another object of the present invention is to disclose such Stibazole compounds（I）And its preparation of pharmaceutically acceptable salt
Method；
Another object of the present invention is to open comprising such Stibazole compounds（I）And its pharmaceutically acceptable salt
Pharmaceutical composition；
Still a further object of the present invention is to disclose such Stibazole compounds（I）And its pharmaceutically acceptable salt is with more
Target spot acts on, the purposes in drug available for preparing treatment and/or prevention nervus retrogression relevant disease, including but not limited to
Vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive
The neurodegenerative diseases such as lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Stibazole compounds disclosed in this invention（I）Chemical structure of general formula be：
In formula：R1And R2Each independently represent H, halogen, C1~C12Alkyl, amino, NR3R4、OR5, trifluoromethyl, trifluoro methoxy
Base, nitro, cyano, carboxyl；R3Represent H, C1~C12Alkyl, propargyl；R4Represent C1~C12Alkyl, propargyl, benzyl or substitution benzyl
Base；NR3R4Nafoxidine base, morpholinyl, piperidyl, 4- be may also indicate that by C1~C12Piperidyl that alkyl is replaced, 4- quilts
Piperidyl that benzyl or substituted benzyl are replaced, piperazinyl, 4- by C1~C12Piperazinyl that alkyl is replaced, 4- by benzyl
Or the piperazinyl that substituted benzyl is replaced；R5Represent H, C1~C12Alkyl, benzyl or substituted benzyl；R1And R2Can arbitrarily may be used in phenyl ring
It can position；Ar represents as follows（A）With（B）Middle any structure unit；
Above-mentioned term " substituted benzyl " refers to the benzyl replaced on phenyl ring by 1-4 groups selected from the group below：F、Cl、Br、
I、C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano, these substituent groups can be in phenyl ring
Arbitrary possible position.
Stibazole compounds proposed by the invention（I）It can be prepared by the following method to obtain：
In formula：R1And R2Definition and chemical structure of general formula（I）It is identical；R1And R2It can be in the arbitrarily possible position of phenyl ring；X is represented
Cl or Br；R6Represent C1-C12Alkyl.
With 5- (halogen methyl) -2,2,8- trimethyls -4H[1,3] dioxane [4,5-c] pyridine compounds and their（1）To rise
Beginning raw material, it is solvent-free or have under solvent condition with phosphite ester（P(OR6)3）Reaction, obtains corresponding picolyl phosphoric acid easter class
Close object（2）；Gained intermediate（2）Under solvent and alkaline condition with corresponding compound of benzaldehyde category（R1R2PhCHO）Condensation,
Obtain isopropyl methene Stibazole compounds（I-1）（Ar is represented in chemical structure of general formula（B）Structural unit）；The change that will be obtained
Close object（I-1）Isopropyl methene protecting group is removed in acidic aqueous solution, obtains Stibazole compounds（I-2）（Chemical constitution
Ar is represented in general formula（A）Structural unit）.
Its specific preparation method is described as follows：
Step a)：5- (halogen methyl) -2,2,8- trimethyls -4H[1,3] dioxane [4,5-c] pyridine compounds and their（1）In nothing
Solvent or have under solvent condition with phosphite ester（P(OR6)3）Reaction, obtains corresponding picolyl phosphoric acid easter class compound（2）；Its
In, reaction solvent for use is：N,NDimethylformamide, dimethyl sulfoxide (DMSO), chlorobenzene, dichloro-benzenes, benzene,toluene,xylene or two
Phenylate；Compound（1）：The molar feed ratio of phosphite ester is 1.0：1.0 ~ 100.0, preferably molar feed ratio is 1.0：1.0~
20.0；Reaction temperature is 50 ~ 250 DEG C, and preferable reaction temperature is 100 ~ 160 DEG C；Reaction time is 30 minutes ~ 24 hours, preferably
Reaction time is 1 ~ 12 hour.
Step b)：The compound being prepared by step a)（2）Under solvent and alkaline condition with compound of benzaldehyde category
（R1R2PhCHO）Condensation, obtains isopropyl methene Stibazole compounds（I-1）（Ar is represented in chemical structure of general formula（B）Structure
Unit）；Wherein, reaction solvent for use is：C1-8Fatty alcohol, ethyl acetate, ether, tetrahydrofuran, 2- methyltetrahydrofurans,N, NDimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane, it is excellent
The solvent is selected to be：Methanol, ethyl alcohol, isopropanol,N,NDimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane or toluene；Reaction
Alkali used is：Alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogen
Compound, C1-8Alkali metal salt, trimethylamine class or the quaternary ammonium bases of alcohol（Such as：Triethylamine, tri-n-butylamine, trioctylamine, pyridine,NMethyl
Morpholine,NMethyl piperidine, triethylene diamine, tetrabutylammonium hydroxide）, preferably alkali is：Potassium hydroxide, sodium hydride, potassium carbonate, three
Ethamine or sodium methoxide；Compound（2）：Compound of benzaldehyde category：The molar feed ratio of alkali is 1.0：0.9~5.0：1.0 ~ 10.0, it is excellent
It is 1.0 to select molar feed ratio：1.0~3.0：1.0~6.0；Reaction temperature is -30 ~ 120 DEG C, and preferable reaction temperature is 0 ~ 100 DEG C；
Reaction time is 1 ~ 24 hour, and preferred reaction time is 2 ~ 12 hours.
Step c)：The isopropyl methene Stibazole compounds being prepared by step b)（I-1）In acidic aqueous solution
Middle removing isopropyl methene protecting group, obtains Stibazole compounds（I-2）（Ar is represented in chemical structure of general formula（A）Structure list
Member）；Wherein, reaction solvent for use is：Water, C1-6Fatty alcohol,N,NDimethylformamide, tetrahydrofuran, C3-8Aliphatic ketone, second
Nitrile, Isosorbide-5-Nitrae-dioxane or dimethyl sulfoxide (DMSO), preferred solvent are：Water, methanol, ethyl alcohol, 1,4- dioxane or tetrahydrofuran；
Acid used is：Hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, C1-6Aliphatic acid, C1-6Alkyl sulfonic acid, benzene sulfonic acid or to first
Benzene sulfonic acid, preferred acid are：Hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, Loprazolam；The mass fraction of acid in the reaction system is 0.1%-
98%, preferred mass score is 10%-95%, and reaction temperature is 0 ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C；Reaction time
It it is 30 minutes ~ 24 hours, preferred reaction time is 1 ~ 8 hour.
The Stibazole compounds of gained according to the method described above（I）In alkalinity, medicine can be passed through with any suitable acid
Its pharmaceutically acceptable salt is made in conventional salifying method on, and the acid is：Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
Phosphoric acid, C1-6Aliphatic carboxylic acid（Such as：Formic acid, acetic acid, propionic acid etc.）, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, amber
Acid, tartaric acid, citric acid, malic acid, lipoic acid, C1-6Alkyl sulfonic acid（Such as：Pyrovinic acid, ethylsulfonic acid etc.）, camphorsulfonic acid,
Benzene sulfonic acid or p-methyl benzenesulfonic acid.
Pharmaceutical composition disclosed in this invention includes one or more Stibazole compounds of therapeutically effective amount
（I）Or its pharmaceutically acceptable salt, the pharmaceutical composition can further contain one or more pharmaceutically acceptable carriers
Or excipient." therapeutically effective amount " refer to cause researcher or targeted tissue, system or the biology of animal of doctor or
The drug of medicine reaction or the amount of medicament；" composition " refers to the production by the way that more than one substances or component mixing are formed
Product；" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable substance, composition or carrier, such as：Liquid or solid
Filler, diluent, excipient, solvent or packing substance, they carry or transport certain chemical substance.It is provided by the present invention
Its ideal ratio of pharmaceutical composition is Stibazole compounds（I）Or its pharmaceutically acceptable salt as activity into
Divide and account for total weight than 2%~99.5%, rest part is accounts for total weight than less than 98%.
Stibazole compounds disclosed in this invention（I）And its pharmaceutically acceptable salt has carried out following life
Object screening active ingredients.
（1）Stibazole compounds（I）To the inhibitory activity of monoamine oxidase A and B
Recombined human MAO-A is made into 12.5 μ g/mL sample liquids with 7.4 kaliumphosphate buffers of pH of 100 mM, MAO-B is made into
75 μ g/mL sample liquids.The addition 20 μ L of testing compound solution into 96 orifice plate of black, 80 μ L of monoamine oxidase, mixing, 37 °
C is incubated 15 min in the place of being protected from light, and adds in 200 μM of Amplex Red reagents, 2U/mL horseradish peroxidases, 2 mM are to hydroxyl
Phenyl ethylamine（Inhibit MAO-A）Or 2 mM benzene methanamines（Inhibit MAO-B）Initiation reaction, 37 °C of 20 min of incubation, in multifunctional enzyme mark
On instrument, to fix 545 nm of excitation wavelength, survey 590 nm places fluorescent emission intensity, with kaliumphosphate buffer instead of MAO-A or
MAO-B is blank；Compound inhibit monoamine oxidase inhibiting rate calculation formula be：100-(IFi)/(IFc) * 100, in formula,
IFiAnd IFcRespectively there are the fluorescence intensities under inhibitor and no inhibitor and the difference of blank fluorescence intensity.Each compound is every
3 multiple holes of secondary measure, every group of experiment are independent in triplicate.Five to six concentration of compound are selected, measure its enzyme inhibition rate, and
With the inhibiting rate linear regression of the negative logarithm of the compound molar concentration and enzyme, molar concentration when acquiring 50% inhibiting rate is
The IC of the compound50.Measurement result shows the Stibazole compounds disclosed in the embodiment of the present invention（I）To MAO-B
It is respectively provided with the effect of significantly inhibiting, IC50For 2.0 nM ~ 20.0 μM；And to the IC of MAO-A inhibition5050.0 μM are above, is said
Bright compound disclosed in this invention has selective inhibitory to MAO-B.
（2）Stibazole compounds（I）Antioxidant activity（ORAC-FL methods）
Reference literature（Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-331）The side reported
Method is measured, i.e.,：6- hydroxyl -2,5,7,8- tetramethyl primary colours alkane -2- carboxylic acids（Trolox）It is made into the PBS buffer solution of pH7.4
The solution of 10-80 μm of ol/L, fluorescein（fluorescein）The solution of 250 nmol/L is made into the PBS buffer solution of pH7.4,
2,2 '-azo diisobutyl amidine dihydrochloride（AAPH）Use the preceding solution that 40 mmol/L are made into the PBS buffer solution of pH7.4.
The compound solution and luciferin solution of 50-10 μm of ol/L, mixing are added in into 96 orifice plates, 37 °C of incubation 15min are added in
AAPH solution makes every hole total volume for 200 μ L, and mixing is immediately placed in multi-function microplate reader, in 485 nm excitation wavelengths and
90 min of METHOD FOR CONTINUOUS DETERMINATION under 535 nm launch wavelengths.Area AUC under fluorescence decay curve is calculated, wherein with 1-8 μm of ol/L'sTroloxAs standard, to be not added with sample to be tested as blank, the antioxidant activity results expression of compound isTroloxEquivalent,
Its calculation formula is：[(AUC Sample-AUC blank)/(AUCTrolox-AUC blank)]´[(concentration
of Trolox/ concentration of sample)], each compound measures 3 multiple holes every time, and every group of experiment is independently heavy
Again three times.Measurement result shows the Stibazole compounds disclosed in the embodiment of the present invention（I）Antioxidant activity beTrolox1.2-3.0 times, illustrate such compound have strong anti-oxidative activity.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention is not limited to
Following embodiments.One of skill in the art, can be right it is understood that under the premise of without departing substantially from the spirit and scope of the present invention
The present invention carries out various change and modification.
Embodiment 1
Ar is represented（B）During structural unit, Stibazole compounds（I-1）Preparation lead to method
4.0 mmol 5- (chloromethyl) -2,2,8- trimethyls -4 are added in reaction bulbH[1,3] dioxane [4,5-c] pyrrole
Pyridine（1）With 25.0 mmol triethyl phosphites, temperature rising reflux is stirred to react 4.0 hours（Reaction process is tracked with TLC）；Reaction
After, remove excessive triethyl phosphite under reduced pressure, residue is purified through silica gel column chromatography（Eluent：Petroleum ether-acetic acid second
Ester=1:1 v/v）, obtain 2,2,8- trimethyls -4H[1,3] dioxane [4,5-c] pyridine -5- methyl acid phosphate diethylesters（2）, receive
Rate 95.0%；
By 2,2,8- trimethyls -4 made from upper stepH[1,3] dioxane [4,5-c] pyridine -5- methyl acid phosphate diethylesters（2）
Full dose is dissolved in 20 ml tetrahydrofurans, is cooled to 0~5 DEG C, adds in 10.0 mmol sodium hydrides, and insulated and stirred is reacted 30 minutes,
Then compound of benzaldehyde category is added in（R1R2PhCHO）4.0 mmol continue at 0~5 DEG C of insulated and stirred and react 6-8 hours；Reaction
After, it adds in 10% aqueous hydrochloric acid solution and terminates reaction, then removed under reduced pressure with 10% soda solution neutralization reaction liquid to neutrality
Tetrahydrofuran, residual solution are extracted with 50 ml ethyl acetate, and organic layer filters after being dried over anhydrous sodium sulfate, and removes solvent under reduced pressure,
Residue is purified through column chromatography（Eluent：Petroleum ether-ethyl acetate=2:1 v/v）, obtain corresponding Stibazole compounds
（I-1）, yield 38.0%-76.0%；Its chemical constitution passes through1H-NMR、13C-NMR and ESI-MS confirmation, gained object it is pure
Degree is all higher than 97.0% through HPLC measure.The object structure being prepared using above-mentioned logical method is as follows：
；
Embodiment 2
Ar is represented（A）During structural unit, Stibazole compounds（I-2）Preparation lead to method
4.0 mmol 5- (bromomethyl) -2,2,8- trimethyls -4 are added in reaction bulbH[1,3] dioxane [4,5-c] pyrrole
Pyridine（1）, 10.0 mmol Trimethyl phosphites and 25 ml chlorobenzenes, temperature rising reflux be stirred to react 5.0 hours（Reaction process TLC
Tracking）；After reaction, excessive Trimethyl phosphite and chlorobenzene are removed under reduced pressure, residue is purified through silica gel column chromatography（Elution
Liquid：Petroleum ether-ethyl acetate=1:1 v/v）, obtain 2,2,8- trimethyls -4H[1,3] dioxane [4,5-c] pyridine -5- methyl
Dimethyl phosphate（2）, yield 88.2%；
By 2,2,8- trimethyls -4 made from upper stepH[1,3] dioxane [4,5-c] pyridine -5- methyl-phosphoric acid dimethyl esters（2）
Full dose is dissolved in 20 ml toluene, is cooled to 0~5 DEG C, adds in 10.0 mmol sodium methoxides, reaction 30 minutes is stirred at room temperature, then
Add in compound of benzaldehyde category（R1R2PhCHO）4.0 mmol are warming up to 50 DEG C and are stirred to react 5-12 hours；After reaction, add
Enter 10% aqueous hydrochloric acid solution and terminate reaction, then with 10% soda solution neutralization reaction liquid to neutrality, remove toluene under reduced pressure, it is remaining
Liquid is extracted with 50 ml ethyl acetate, and organic layer filters after being dried over anhydrous sodium sulfate, and removes solvent under reduced pressure, residue is through column layer
Analysis purifying（Eluent：Petroleum ether-ethyl acetate=2:1 v/v）, obtain accordingly corresponding Stibazole compounds（I-
1）, yield 30.0%-82.0%；
By Stibazole compounds made from upper step（I-1）Full dose adds in 10 ml, 15% aqueous hydrochloric acid solutions and 20 ml ethyl alcohol
Mixed solution in, reaction is stirred at room temperature 3.0~7.0 hours（Reaction process is tracked with TLC）, after reaction, remove under reduced pressure
Solvent, adds in 50 ml ethyl acetate in residue, organic layer successively with 25 ml, 5% sodium bicarbonate aqueous solutions and 20 ml go from
Sub- water washing filters after being dried over anhydrous sodium sulfate, and removes solvent under reduced pressure, and residue is purified through column chromatography（Eluent：Oil
Ether-ethyl acetate=2:1 v/v）, obtain corresponding Stibazole compounds（I-2）, yield 83.5%-93.0%；Its chemistry knot
Structure passes through1H-NMR、13C-NMR and ESI-MS confirmations, the purity of gained object are all higher than 97.0% through HPLC measure.Using upper
It is as follows to state the object structure that logical method is prepared：
3 Stibazole compounds of embodiment（I）With acid logical method is prepared into salt
The Stibazole compounds according to 1 or 2 gained of above-described embodiment are added in reaction bulb（I）2.0 mmol and methanol
50 ml, are stirring evenly and then adding into that 6.0 mmol are sour accordingly, and temperature rising reflux is stirred to react 10 minutes, is cooled to after reaction
Room temperature, removes solvent under reduced pressure, and residue acetone recrystallization filters the solid of precipitation to get Stibazole compounds（I）
Salt, chemical constitution warp1H NMR and ESI-MS are confirmed.
Claims (9)
1. a kind of Stibazole compounds or its pharmaceutically acceptable salt, it is characterised in that the chemistry knot of such compound
Structure general formula is such as（I）It is shown：
In formula：R1And R2Each independently represent H, halogen, C1~C12Alkyl, amino, NR3R4、OR5, trifluoromethyl, trifluoro methoxy
Base, nitro, cyano, carboxyl；R3Represent H, C1~C12Alkyl, propargyl；R4Represent C1~C12Alkyl, propargyl, benzyl or substitution benzyl
Base；NR3R4Nafoxidine base, morpholinyl, piperidyl, 4- be may also indicate that by C1~C12Piperidyl that alkyl is replaced, 4- quilts
Piperidyl that benzyl or substituted benzyl are replaced, piperazinyl, 4- by C1~C12Piperazinyl that alkyl is replaced, 4- by benzyl
Or the piperazinyl that substituted benzyl is replaced；R5Represent H, C1~C12Alkyl, benzyl or substituted benzyl；R1And R2Can arbitrarily may be used in phenyl ring
It can position；Ar represents as follows（A）With（B）Middle any structure unit；
" substituted benzyl " refers to the benzyl replaced on phenyl ring by 1-4 groups selected from the group below：F、Cl、Br、I、C1-4
Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano, these substituent groups can appointing in phenyl ring
Meaning possible position.
2. Stibazole compounds as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that described
Pharmaceutically acceptable salt quasi-styrene pyridine compounds and their and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C thus1-6Fat
Fat carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lipoic acid,
C1-6Alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid salt.
3. the preparation side of Stibazole compounds or its pharmaceutically acceptable salt as described in claim any one of 1-2
Method, it is characterised in that the compound can be prepared by the following method to obtain：
In formula：R1And R2Definition and chemical structure of general formula（I）It is identical；R1And R2It can be in the arbitrarily possible position of phenyl ring；X represents Cl
Or Br；R6Represent C1-C12Alkyl；
Step a)：5- (halogen methyl) -2,2,8- trimethyls -4H[1,3] dioxane [4,5-c] pyridine compounds and their（1）In nothing
Solvent or have under solvent condition with phosphite ester（P(OR6)3）Reaction, obtains corresponding picolyl phosphoric acid easter class compound（2）；
Step b)：The compound being prepared by step a)（2）Under solvent and alkaline condition with compound of benzaldehyde category
（R1R2PhCHO）Condensation, obtains Stibazole compounds（I-1）；
Step c)：The Stibazole compounds being prepared by step b)（I-1）Isopropyl first is removed in acidic aqueous solution
Protecting group is pitched, obtains Stibazole compounds（I-2）；
Utilize the Stibazole compounds of above two method gained（I）Contain basic group in molecule, it can be with any conjunction
Its pharmaceutically acceptable salt is made by pharmaceutically conventional salifying method in suitable acid.
4. the preparation method of Stibazole compounds as claimed in claim 3 or its pharmaceutically acceptable salt, feature
It is in step a), reaction solvent for use is：N,NDimethylformamide, dimethyl sulfoxide (DMSO), chlorobenzene, dichloro-benzenes, benzene, toluene,
Dimethylbenzene or diphenyl ether；Compound（1）：The molar feed ratio of phosphite ester is 1.0：1.0~100.0；Reaction temperature is 50 ~ 250
℃；Reaction time is 30 minutes ~ 24 hours.
5. the preparation method of Stibazole compounds as claimed in claim 3 or its pharmaceutically acceptable salt, feature
It is in step b), reaction solvent for use is：C1-8Fatty alcohol, ethyl acetate, ether, tetrahydrofuran, 2- methyltetrahydrofurans,N,NDimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane；
Alkali is used in reaction：Alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali gold
Belong to hydride, C1-8The alkali metal salt of alcohol, triethylamine, tri-n-butylamine, trioctylamine, pyridine,NMethyl morpholine,NMethyl piperidine, three second
Alkene diamines, tetrabutylammonium hydroxide；Compound（2）：Compound of benzaldehyde category：The molar feed ratio of alkali is 1.0：0.9~5.0：
1.0~10.0；Reaction temperature is -30 ~ 120 DEG C；Reaction time is 1 ~ 24 hour.
6. the preparation method of Stibazole compounds as claimed in claim 3 or its pharmaceutically acceptable salt, feature
It is in step c), reaction solvent for use is：Water, C1-6Fatty alcohol,N,NDimethylformamide, tetrahydrofuran, C3-8Aliphatic ketone,
Acetonitrile, 1,4- dioxane or dimethyl sulfoxide (DMSO)；Acid used is：Hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, C1-6
Aliphatic acid, C1-6Alkyl sulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid；The mass fraction of acid in the reaction system is 0.1%-98%, is reacted
Temperature is 0 ~ 150 DEG C；Reaction time is 30 minutes ~ 24 hours.
7. a kind of pharmaceutical composition, it is characterised in that include such as claim 1-2 any one of them styryl pyridine class chemical combination
Object or its pharmaceutically acceptable salt, the pharmaceutical composition further contain one or more pharmaceutically acceptable carriers or tax
Shape agent.
8. pharmaceutical composition as claimed in claim 7, it is characterised in that the Stibazole compounds or its pharmaceutically
Acceptable salt accounts for total weight than 5%~99.5% as active constituent.
9. as claim 1-2 any one of them Stibazole compounds or its pharmaceutically acceptable salt are controlled in preparation
It treats and/or prevents the purposes in nervus retrogression relevant disease drug, this kind of nervus retrogression relevant disease is：Vascular is crazy about
Slow-witted, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive funiculus lateralis medullae spinalis
Sclerosis, neuropathic pain or glaucoma.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111087386A (en) * | 2020-01-02 | 2020-05-01 | 牡丹江医学院 | Compound for treating Alzheimer disease and synthetic method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111087386A (en) * | 2020-01-02 | 2020-05-01 | 牡丹江医学院 | Compound for treating Alzheimer disease and synthetic method thereof |
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